Especially, 2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-yl}methyl)sulfanyl]phenoxy}acetic acid (hereinafter, called to “GW501516”) among thiazole derivatives of formula (I) showed an excellent effect to treatment of obesity in animal models (Cell 2003, 113, 159), and proved effectiveness in cardiovascular disease by increasing high density lipoprotein (HDL) and decreasing low density lipoprotein (LDL) effectively in the animal experiment (Proc. Natl. Acad. USA 2001, 98, 5306) and in clinical trial. And the process for preparation of the said substance has been disclosed in PCT publication WO 01/00603A 1, Bioorg. Med. Chem. Lett. 2003, 13, 1517 and J. Chem. Org. 2003. 68. 9116, in which GW501516 (13) was prepared, as shown in the following scheme (1). Methyl (4-mercapto-3-methylphenoxy)acetate (7), synthesized from the starting material, 4-hydroxy-3-methylacetophenone (1), via 6 steps, was coupled to 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)thiazole (11), which was prepared from 4-(trifluoromethyl)thiobenzamide (8) via 3 steps, in the presence of excessive cesium carbonate to obtain the methyl ester (12) of GW501516, and then treating the ester with 1 N lithium hydroxide to give GW501516.

As an alternative synthesis method of GW501516, it is disclosed, as illustrated in the following scheme (2), that the compound (13) of GW501516 can be prepared by introducing ethyl acetate group to o-cresol (14), reacting the resulted compound (15) with sulfonyl chloride, reducing the resulted compound (16) with tin (Sn) under acidic condition to form ethyl (4-mercapto-2-methyl phenoxy)acetate (17), reacting it with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl phenyl)thiazole (11) together with an excessive cesium carbonate to obtain the ethyl ester intermediate (18) of GW501516, and deprotecting the ester group of the intermediate compound with 1N lithium hydroxide.

As another alternative synthesis method of GW501516, it is disclosed, as illustrated in the following scheme (3), that the compound (13) of GW501516 can be prepared by reacting o-cresol with sodium thiocynate in the presence of bromine, reducing the resulted compound with lithium aluminium hydride to form 4-mercapto-2-methylphenol (20), reacting it with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl phenyl)thiazole (11) and methylbromoacetate sequentially to obtain the ethyl ester intermediate (12) of GW501516, and deprotecting the ester group of the intermediate compound with 2 M lithium hydroxide.
